The long term objective of the proposed research is to provide the chemical and biochemical basis for the determination of the toxicity of the nitrogen oxides and nitrosyl compounds. Chemical oxidations resulting from the action of nitrogen oxides and nitrosyl compounds on hemoproteins will be investigated. The mechanism of oxyhemoprotein oxidations by the nitrite ion, in which monomeric nitrogen dioxide and the peroxynitrate ion are implicated as intermediates, will be defined, and the chemical characteristics of peroxynitrate will be established. Kinetically based structure-activity relationships for the broad classification of nitrosyl derivatives, that include alkyl nitrites, nitrosamides, nitrosamines, and C-nitroso compounds, in their oxidative reactions with hemoproteins will be obtained. These investigations will establish the nature of structural influences on hemoprotein oxidations, provide quantitative characterization of the association of nitrosyl compounds with hemoproteins, and further define the different oxidative susceptibilities of the R and T conformational states of hemoglobin. Parallel studies of metalloprotein oxidations of thioureas and investigations of the oxidative activities of dithiodicarbenium salts, which are directed to a mechanistic understanding of the medicinal and potential chemical side effects of thiourea drugs, will be undertaken. Ligand transfer reactions will be employed to further define the mechanism of nitric oxide oxidations of oxyhemoproteins, to determine equilibrium constants for oxygen association with hemoproteins, to investigate the mechanism of hemoprotein oxidations by cobalt-dioxygen complexes, and to establish the extent to which hemoglobin serves as a carrier of diverse chemical substances for circulatory distribution. The formation of thionitrosyl compounds and their nitrosative transformations will be examined. The thiol group is expected to function as catalyst for nitrosative rpocesses, and methods that will determine the nature and extent of these reactions in proteins containing accessible thiol groups will be developed.